title: Difluoromethylornithine is a novel inhibitor of Helicobacter pylori growth, CagA translocation, and interleukin-8 induction.
abstract: Helicobacter pylori infects half the world's population, and carriage is lifelong without antibiotic therapy. Current regimens prescribed to prevent infection-associated diseases such as gastroduodenal ulcers and gastric cancer can be thwarted by antibiotic resistance. We reported that administration of 1% D,L-α-difluoromethylornithine (DFMO) to mice infected with H. pylori reduces gastritis and colonization, which we attributed to enhanced host immune response due to inhibition of macrophage ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis. Although no ODC has been identified in any H. pylori genome, we sought to determine if DFMO has direct effects on the bacterium. We found that DFMO significantly reduced the growth rate of H. pylori in a polyamine-independent manner. Two other gram-negative pathogens possessing ODC, Escherichia coli and Citrobacter rodentium, were resistant to the DFMO effect. The effect of DFMO on H. pylori required continuous exposure to the drug and was reversible when removed, with recovery of growth rate in vitro and the ability to colonize mice. H. pylori exposed to DFMO were significantly shorter in length than those untreated and they contained greater internal levels of ATP, suggesting severe effects on bacterial metabolism. DFMO inhibited expression of the H. pylori virulence factor cytotoxin associated gene A, and its translocation and phosphorylation in gastric epithelial cells, which was associated with a reduction in interleukin-8 expression. These findings suggest that DFMO has effects on H. pylori that may contribute to its effectiveness in reducing gastritis and colonization and may be a useful addition to anti-H. pylori therapies.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Barry
authors.forename: Mohammad
authors.initials: M
authors.lastname: Asim
authors.forename: David A
authors.initials: DA
authors.lastname: Leiman
authors.forename: Thibaut
authors.initials: T
authors.lastname: de Sablet
authors.forename: Kshipra
authors.initials: K
authors.lastname: Singh
authors.forename: Robert A
authors.initials: RA
authors.lastname: Casero
authors.forename: Rupesh
authors.initials: R
authors.lastname: Chaturvedi
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D000518:Eflornithine / Q000494:pharmacology* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005753:Gastric Mucosa / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D005756:Gastritis / Q000382:microbiology / Q000517:prevention & control; D016481:Helicobacter Infections / Q000235:genetics / Q000378:metabolism / Q000382:microbiology* / Q000517:prevention & control; D016480:Helicobacter pylori / Q000187:drug effects* / Q000254:growth & development* / Q000502:physiology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D021381:Protein Transport / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D016209:Interleukin-8; C080866:cagA protein, Helicobacter pylori; D000518:Eflornithine